Use of phthalyltaurine sulfonamide derivatives in treating epilepsy and arrythmia

ABSTRACT

PCT No. PCT/FI81/00037 Sec. 371 Date Jan. 11, 1982 Sec. 102(e) Date Jan. 11, 1982 PCT Filed May 22, 1981 PCT Pub. No. WO81/03492 PCT Pub. Date Dec. 10, 1981.The invention relates to taurine derivatives with the chemical structure:  &lt;IMAGE&gt;  where R1=H R2=a lower alkyl group with up to 4 carbonatoms or an acetyl group or where  &lt;IMAGE&gt;  These compounds were found in pharmacological studies to have qualities which make them useful as drugs.

The present invention relates to taurine derivatives, their production,and their use in drugs. The compounds are phthalyltaurine sulfonamideswith the chemical structure: ##STR3## where

R₁ =H,

R₂ =a lower alkyl group with up to 4 carbonatoms or an acetyl group,

or where ##STR4##

The new compounds synthesized by us are:

2-Phthalimidoethanesulfone methylamide

2-Phthalimidoethanesulfone ethylamide

2-Phthalimidoethanesulfone n-propylamide

2-Phthalimidoethanesulfone isopropylamide

2-Phthalimidoethanesulfone n-butylamide

2-Phthalimidoethanesulfone pyrrolidide.

In addition, we have synthesized the following compounds previouslydescribed in the literature: 2-phthalimidoethane sulfonamide,2-phthalimidoethanesulfone dimethylamide, 2-phthalimidoethanesulfonetertbutylamide and 2-phthalimidoethane sulfonylacetamide, which werefound in pharmacological studies to have the same good drug qualities asthe present new compounds.

Taurine, 2-aminoethanesulfonic acid, occurs in rich amounts in humantissues. Particularly high concentrations are found in the spleen,muscles, and brain (Jacobsen J. C. & Smith L. J., Jr Physiol. Rev 48,424-511, 1968). There is good reason to believe that taurine acts as aninhibitory neurotransmitter in the central nervous system. The role oftaurine is not yet definitely clarified. Decreased taurineconcentrations have been observed in some cases of epilesy. Taurine hasbeen found to have a direct central anticonvulsive effect in severaltypes of experimental epilepsy. A Barbeau & Donaldson (Arch. Neurol. 30,50-58, 1974) and R. Takahaski & Y. Nakane (Taurine and NeurologicalDisorders, 375-385, 1978) have demonstrated an antiepileptic action oftaurine in the treatment of epileptic patients.

As taurine is an extremely hydrophilic compound, it seems unlikely thatadministered external taurine could penetrate into the brain in largeenough amounts to produce a direct anticonvulsive effect in epilepticpatients with intact bloodbrain barrier. Thus, to reach the brain insufficient quantities, taurine must be given intracerebrally.

The present taurine derivatives are considerably more lipophilic thantaurine, but they still have the same anticonvulsive properties. Thesynthesized compounds have been shown in pharmacological tests to have agood anticonvulsive effect. Theoretically, thus, it appears that theycould be of value in antiepileptic therapy. The compounds have also beenfound antiarrhythmically active.

The pharmacological actions of taurine derivatives are only sparinglydescribed i the literature. J. F. Mead & J. B. Koepfli (J. Org. Chem.12, 295-297, 1947) have synthesized pantoyl taurinamide and2-phthalimido-N-bimethylathane sulfonamide and studied their effect inmalaria. R. Winterbottom et al. (J.A.C.S. 69, 1393-1401, 1947)synthesized 2-phthalimidoethane sulfonamide and2-phthalimidoethanesulfone dimethylamide and studied their antibacterialproperties, which did not come up to expectations.

J. W. Griffin & D. H. Hey (J. Chem.Soc. 3334-3340, 1952) describe thesynthesis of 2-phthalimidoethanesulfonyl acetamide.

Of more recent publications the following could be mentioned: TheEuropean patent application no. 0 002 675 (P. H. Chakrabarti, GAFCorporation, 1979) relates to the production of salt-free N-acyltaurines used as surface-active agents. The French patent publicationno. 2412523 (P. Reynard, 1979) relates to injectable forms of N-acetyltaurine, which in pharmacological tests were found to penetrate thebloodbrain barrier.

Gamma-L-glutamyl taurine, whose effect resembles that of vitamin A, hasbeen tested by L. Feuer (Comp. Biochem. Physiol. 62 A, 995-997, 1979)among others. Liisa Ahtee et al. (Proc. B.P.S., Brit. J. Pharmacol.480P, 1979) have studied the effect of various taurine derivatives onthe central nervous system of mice after intraperitoneal administration.They found that N-pivaloyl taurine penetrated the blood-brain barrier.

The present invention is characterized by that the new compounds withthe above-described pharmacological properties are synthesized

(A) by conversion of phthalimidoethane sulfonylchloride with a primaryamine through the following reaction: ##STR5## where R is a methyl-,ethyl-, n-propyl-, isopropyl- or n-butylgroup

(B) by conversion of phthalimidoethane sulfonylchloride with a secondaryamine or pyrrolidine: ##STR6## where ##STR7##

(C) by alkylation of phthalimidoethane sulfonamide with known alkylatingagents such as alkyl halogenides, dialkyl sulfate, etc.: ##STR8## where

X is a halogen,

R is a methyl-, ethyl-, n-propyl-, isopropyl- or n-butylgroup.

In addition, 2-phthalimidoethane sulfonamide, 2-phthalimidoethanesulfonedimethylamide, 2-phthalimidoethanesulfone tert-butylamide and2-phthalimidoethanesulfonyl acetamide, which in pharmacologicalscreening tests were found to have the same valuable properties as thepresent new compounds, were synthesized by a previously known method.

The purity of the compounds was tested by thinlayer chromatography.Elementary analysis of all the new compounds was performed, and theirIR, UV and NMR spectra were recorded.

The following examples illustrate the invention in more detail:

EXAMPLE 1 2-Phthalimidoethanesulfone methylamide

13.70 g of phthalimidoethanesulfonylchloride is dissolved in 200 ml ofmethylene chloride. Under stirring and cooling to 15°-20° C., a currentof gaseous methylamine is conducted through the solution for 0.5 h. Thesolvent is evaporated, water is added to the solution, and theprecipitate formed is filtered off, washed with water and dried.Recrystallization from ethanol yields 10.91 g of sulfonamide, m.p.142°-144° C.

The yield is 81% of the theoretical. Calculated for C₁₁ H₁₂ N₂ O₄ S:C=49.2, H=4.5, N=10.4, S=12.0, Obtained: C=49.3, H=4.4, N=10.4, S=12.0.

EXAMPLE 2 2-Phthalimidoethanesulfone methylamide

Another method of preparing 2-phthalimidoethanesulfone methylamide is bya two-phase reaction in the following way:

To a mixture of 2.74 g of phthalimidoethane sulfonylchloride and 1.36 gof methylamine hydrochloride in 30 ml of methylene chloride there isadded 7 ml of saturated potassium carbonate solution, and the mixture isstirred thoroughly for 10 minutes, after which the organic phase isseparated, washed with water and dried, and the clear solution isevaporated. Yield: 2.14 g=80% of theoretical; m.p. 142°-144° C.

EXAMPLE 3 2-Phthalimidoethanesulfone ethylamide

8.21 g of 2-phthalimidoethane sulfonylchloride is dissolved in 70 ml ofmethylene chloride, and 3.00 g of ethylamine in 10 ml of methylenechloride. The solutions are cooled to 4° C., combined, and stirred for30 minutes; the temperature rises to approximately 27° C. Afterevaporation of the reaction mixture, water is added and the precipitateformed is filtered off and washed. Recrystallization from ethanol yields6.31 g of sulfonamide, melting at 111°-114° C.; 79% of theoreticalyield.

Calculated for C₁₂ H₁₄ N₂ O₄ S: C=51.2, H=5.0, N=9.9, S=11.4; obtainedC=51.2, H=5.0, N=10.0, S=11.4.

EXAMPLE 4 2-Phthalimidoethanesulfone ethylamide

To a mixture of 2.74 g of phthalimidoethane sulfonylchloride and 1.23 gof ethylamine hydrochloride in 30 ml of methylene chloride there isadded 7 ml of saturated potassium carbonate solution and the mixture isstirred thoroughly for 10 minutes, after which the organic phase isseparated, washed with water, dried and evaporated. Recrystallizationyields 2.15 g of a product melting at 111°-114° C. The yield is 76% ofthe theoretical.

EXAMPLE 5 2-Phthalimidoethanesulfone n-propylamide

8.22 g of 2-phthalimidoethane sulfonylchloride, 4.02 g of n-propylaminehydrochloride, 120 ml of methylene chloride and 21 ml of saturatedpotassium carbonate solution are prepared as in Example 2.Recrystallization from 90% ethanol and ethylacetate yields 4.87 g ofsulfonamide, m.p. 112°-114° C. Yield 55% of theoretical.

Calculated for C₁₃ H₁₆ N₂ O₄ S: C=52.7, H=5.4, N=9.5, S=10.8; obtainedC=52.9, H=5.4, N=9.5, S=10.8.

EXAMPLE 6 2-Phthalimidoethanesulfone isopropylamide

To 21 ml of saturated potassium carbonate solution there is added 45 mlof methylene chloride and 2.48 g of isopropylamine. 8.22 g of2-phthalimidoethane sulfonylchloride is dissolved in 45 ml of methylenechloride and added to the reaction mixture. Recrystallization fromethanol yields 8.01 g of sulfonamide, m.p. 137°-139° C.; 90% oftheoretical yield.

Calculated for C₁₃ H₁₆ N₂ O₄ S: C=52.7, H=5.4, N=9.5, S=10.8; obtainedC=53.0, H=5.5, N=9.5, S=10.9.

EXAMPLE 7 2-Phthalimidoethanesulfone n-butylamide

To a mixture of 2.40 g of phthalimidoethane sulfonylchloride and 25 mlof methylene chloride there is added 1.00 g of n-butylamine andimmediately afterwards, under stirring, 20 ml of 2.8N sodium carbonatesolution. After this the mixture is stirred for 10 minutes and theorganic phase is separated, washed with water, dried, and evaporated.Recrystallization from cyclohexane yields 1.85 g, m.p. 71°-73° C. Yield68% of theoretical.

Calculated for C₁₄ H₁₈ N₂ O₄ S: C=54.2, H=5.8, N=9.0, S=10.3; obtainedC=52.3, H=5.8, N=9.1, S=10.3.

EXAMPLE 8 2-Phthalimidoethanesulfone tert-butylamide

36.1 g of 2-phthalimidoethane sulfonylchloride in 98.2 ml of pyridine iscooled to 0°-3° C. 4.3 g of tert-butylamine is added under stirring, andthe mixture is kept cool for 0.5 h and then at room temperature for 2 h.The reaction mixture is poured on a mixture of 300 g of ice, 70 ml ofwater, and 130 ml of concentrated hydrochloric acid. The precipitateformed is filtered off, washed with water, dried, and washed with ether.Recrystallization from ethylacetate yields 27.5 h og sulfonamide meltingat 163°-165° C. Yield 68% of theoretical.

Calculated for C₁₄ H₁₈ N₂ O₄ S: C=54.2, H=5.8, N=9.0, S=10.3, Obtained:C=54.2, H=5.9, N=9.1, S=10.3.

EXAMPLE 9 2-Phthalimidoethanesulfone pyrrolidide

Of 6.48 g of 2-phthalimidoethane sulfonylchloride, about half thequantity is added to a mixture of 40 ml of acetonitrile and 2.1 ml ofpyrrolidine; the temperature rises to 42° C. Another 2.1 ml ofpyrrolidine is added, and the temperature rises to 48° C. The remaining2-phthalimidoethane sulfonylchloride is added. When the reaction beginsto slacken, the mixture is heated under reflux for 2.5 h, after which itis cooled and filtered. Water is added, and the precipitate formed isfiltered off. Recrystallization from ethylacetate yields 2.97 g ofamide, melting at 176°-178° C. Yield 39% of theoretical.

Calculated for C₁₄ H₁₆ N₂ O₄ S: C=54.5, H=5.2, N=9.1, S=10.4, Obtained:C=54.4, H=5.2, N=9.1, S=10.4.

EXAMPLE 10 2-Phthalimidoethanesulfone pyrrolidide

Alternatively, 2-phthalimidoethanesulfone pyrrolidide may be prepared inthe following way:

A mixture of 1.27 g of 2-phthalimidoethane sulfonamide, 0.6 ml of1.4-dibromobutane, 1.38 g of potassium carbonate, 10 ml of acetonitrileand about 0.05 g of potassium iodide is heated for 37 h under reflux andstirring, after which there is added to the reaction mixture 25 ml ofwater, 5 ml of 3N hydrochloric acid and 15 ml of methylene chloride. Theorganic phase is separated and treated first with 15 ml of 3N sodiumcarbonate then with water, dried, and evaporated. After washing withethanol and recrystallization, 0.74 g of pyrrolidide is obtained; m.p.177°-179° C. Yield 51% of theoretical.

EXAMPLE 11 2-Phthalimidoethanesulfone methylamide

A mixture of 1.27 g of 2-phthalimidoethane sulfonamide, 0.30 ml ofdimethyl sulfate, 0.35 g of potassium carbonate and 10 ml ofacetonitrile is heated under stirring and reflux. After 0.5 h there isadded 0.18 ml of dimethyl sulfate. The mixture is allowed to react foranother hour, after which 20 ml of water, 5 ml of 3N hydrochloric acidand 15 ml of methylene chloride are added. The organic phase is treatedwith sodium carbonate solution and water, dried, and evaporated.Recrystallization from ethanol yields 0.39 g of sulfonamide, melting at139°-141° C. Yield 31% of theoretical.

The anticonvulsive effect of the compounds was studied on three types ofexperimental epilepsy. Convulsions were induced in mice by subcutaneousadministration of pentylene tetrazole or strychnine, or by electricalstimulation with a 50 mA current (E. A. Swinyard, Assay of antiepilepticdrug activity in experimental animals: Standard tests in InternationalEnocyclopedica of Pharmacology and Therapeutics, Section 19, vol 1:Anticonvulsant Drugs, 1972). Several compounds protected againstconvulsions in all three tests after oral as well as intraperitonealadministration. ED₅₀ (the dose effective in 50% of the treated animals)ranged from 103 mg/kg to >300 mg/kg (table I). No sedative effect couldbe observed.

                  TABLE I                                                         ______________________________________                                        Antiepileptic screening                                                                     Anticonvulsive activity                                                         ED.sub.50  mg/kg   i.p.                                       Compound        MES        MET     STR                                        ______________________________________                                        2-Phthalimidoethanesulfone                                                                     122       >300     93                                        amide                                                                         2-Phthalimidoethanesulfone                                                                    >300       >300    --                                         tert-butylamide                                                               2-Phthalimidoethanesulfone                                                                    >300       >300    --                                         pyrrolidide                                                                   2-Phthalimidoethanesulfonyl                                                                   >300       >300    --                                         acetamide                                                                     2-Phthalimidoethanesulfone                                                                    112         170    189                                        methylamide                                                                   2-Phthalimidoethanesulfone                                                                    113         231    234                                        dimethylamide                                                                 2-Phthalimidoethanesulfone                                                                    219        >300    --                                         n-butylamide                                                                  2-Phthalimidoethanesulfone                                                                    103         138    126                                        ethylamide                                                                    2-Phthalimidoethanesulfone                                                                    130        >300    227                                        isopropylamide                                                                2-Phthalimidoethanesulfone                                                                    252        >300    >300                                       n-propylamide                                                                 ______________________________________                                         MES = maximal electroshock test                                               MET = metrazole (= pentylene tetrazole) convulsant threshold test.            STR = strychnine convulsant threshold test                               

Isolated perfused rat heart, prepared after the method of Langendorff,and isolated spontaneously beating rat atria (W. C. Holland & J. H.Burn, J. Brit. Med., vol 1, 1031, 1958) were used for studies of theantiarrhythmic effect of the compounds. Arrhythmia was induced by K⁺deficiency and by aconitine. A clear antiarrhythmic effect wasdemonstrated (tables II and III). Some of the compounds had a bettereffect than the reference substances lidocaine, quinidine, andpropranolol. Besides the above-described in vitro tests, an in vivomethod was used: the antiarrhythmic effect of the compounds was studiedin quineapigs with ouabain-induced arrhythmia. When the quinea-pigs hadbeen treated with the new compounds, larger doses of ouabain wererequired to induce arrhythmia (table IV). Propranolol, which was used asa reference substance in test, caused bradycardia, which the testsubstances did not.

                  TABLE II                                                        ______________________________________                                        Effect of the test compounds on arrhythmia induced by                         K.sup.+  deficiency in perfused Langendorff's rat heart.                                                     Development of                                                                arrhythmia. Per-                                                      Conc.   centage change in                              Compound        N      M       time                                           ______________________________________                                        Lidocaine       5      10.sup.-4                                                                             +30,9                                          2-Phthalimidoethanesulfone                                                                    3      "       +23,6                                          amide                                                                         2-Phthalimidoethanesulfone                                                                    3      "       +8,5                                           tert-butylamide                                                               2-Phthalimidoethanesulfone                                                                    3      "       +0,2                                           pyrrolidide                                                                   2-Phthalimidoethanesulfonyl                                                                   3      "       +26,3                                          acetamide                                                                     2-Phthalimidoethanesulfone                                                                    3      "       +22,7                                          methylamide                                                                   2-Phthalimidoethanesulfone                                                                    2      "       -5,1                                           dimethylamide                                                                 2-Phthalimidoethanesulfone                                                                    4      "       +4,9                                           n-butylamide                                                                  2-Phthalimidoethanesulfone                                                                    2      "       -4,7                                           ethylamide                                                                    2-Phthalimidoethanesulfone                                                                    2      "       -10,1                                          isopropylamide                                                                2-Phthalimidoethanesulfone                                                                    3      "       +10,3                                          n-propylamide                                                                 ______________________________________                                    

                  TABLE III                                                       ______________________________________                                        Ability of the test compounds to protect against develop-                     ment of arrhythmia in spontaneously beating isolated rat                      atria after addition of 2.5 × 10.sup.-5 M aconitine.                                                 Development of                                                                arrhythmia                                                          Conc.     Time in seconds ±                             Compound     N     M         SE Δ sec.                                  ______________________________________                                        Control      8     --                                                         Quinidine    3     5 × 10.sup.-4                                                                     267 ± 71                                                                           +71                                       "           7     1 × 10.sup.-4                                                                     450 ± 59                                                                           +243                                      "           2     5 × 10.sup.-5                                                                     225 ± 20                                                                           +18                                      Propranolol  2     5 × 10.sup.-4                                                                     105 ± 50                                                                           -102                                      "           3     1 × 10.sup.-4                                                                     325 ± 16                                                                           +118                                      "           3     5 × 10.sup.-5                                                                     301 ± 80                                                                           +94                                       "           2     1 × 10.sup.-5                                                                     245 ± 50                                                                           +38                                      Lidocaine    2     5 × 10.sup.-4                                                                       95 ± 45                                                                          -112                                      "           2     1 × 10.sup.-4                                                                     295 ± 75                                                                           +88                                       "           2     5 × 10.sup.-5                                                                     335 ± 5                                                                            +128                                      "           2     1 × 10.sup.-5                                                                     200 ± 35                                                                           -7                                       2-Phthalimidoethane-                                                                       3     5 × 10.sup.-4                                                                     397 ± 86                                                                           +190                                     sulfone amide                                                                 2-Phthalimidoethane-                                                                       3     1 × 10.sup.-4                                                                     222 ± 76                                                                           +15                                      sulfone amide                                                                 2-Phthalimidoethane-                                                                       2     1 × 10.sup.-3                                                                     >900    >+693                                    sulfone methylamide                                                           2-Phthalimidoethane-                                                                       3     5 × 10.sup.-4                                                                     420 ± 53                                                                           +213                                     sulfone methylamide                                                           2-Phthalimidoethane-                                                                       3     1 × 10.sup.-4                                                                     445 ± 85                                                                           +238                                     sulfone methylamide                                                           2-Phthalimidoethane-                                                                       3     5 × 10.sup.-5                                                                     290 ± 52                                                                           +83                                      sulfone methylamide                                                           2-Phthalimidoethane-                                                                       2     5 × 10.sup.-4                                                                     222 ± 50                                                                           +15                                      sulfone dimethylamide                                                         2-Phthalimidoethane-                                                                       3     1 × 10.sup.-4                                                                     143 ± 38                                                                           -64                                      sulfone dimethylamide                                                         2-Phthalimidoethane-                                                                       2     5 × 10.sup.-5                                                                     217 ± 50                                                                           +10                                      sulfone dimethylamide                                                         2-Phthalimidoethane-                                                                       3     1 × 10.sup.-4                                                                     751 ± 49                                                                           +544                                     sulfone ethylamide                                                            2-Phthalimidoethane-                                                                       3     7,5 × 10.sup.-5                                                                    326 ± 171                                                                         +119                                     sulfone ethylamide                                                            2-Phthalimidoethane-                                                                       3     5 × 10.sup.-5                                                                     160 ± 55                                                                           -47                                      sulfone ethylamide                                                            2-Phthalimidoethane-                                                                       3     5 × 10.sup.-4                                                                     441 ± 59                                                                           +234                                     sulfone n-propylamide                                                         2-Phthalimidoethane-                                                                       4     1 × 10.sup.-4                                                                     488 ± 45                                                                           +281                                     sulfone n-propylamide                                                         2-Phthalimidoethane-                                                                             5 × 10.sup.-5                                                                     278 ± 94                                                                           +71                                      sulfone n-propylamide                                                         2-Phthalimidoethane-                                                                       4     1 × 10.sup.-4                                                                     >900    >+693                                    sulfone isopropylamide                                                        2-Phthalimidoethane-                                                                       3     5 × 10.sup.-5                                                                     676 ± 27                                                                           +469                                     sulfone isopropylamide                                                        2-Phthalimidoethane-                                                                             1 × 10.sup.-5                                                                     225 ± 17                                                                           +18                                      sulfone isopropylamide                                                        2-Phthalimidoethane-                                                                       3     1 × 10.sup.-3                                                                     >900    >+693                                    sulfone n-butylamide                                                          2-Phthalimidoethane-                                                                       3     5 × 10.sup.-4                                                                      508 ± 120                                                                         +301                                     sulfone n-butylamide                                                          2-Phthalimidoethane-                                                                       3     1 × 10.sup.-4                                                                      258 ± 114                                                                         +51                                      sulfone n-butylamide                                                          2-Phthalimidoethane-                                                                       4     5 × 10.sup.-4                                                                     246 ± 74                                                                           +39                                      sulfonyl acetamide                                                            2-Phthalimidoethane-                                                                       3     1 × 10.sup.-4                                                                     192 ± 36                                                                           -15                                      sulfonyl acetamide                                                            ______________________________________                                    

                                      TABLE IV                                    __________________________________________________________________________    Ability of the test compounds to protect against development of               arrhythmia in guinea-pigs                                                     after infusion of ouabain 20 μg/kg/min.                                                                HR, beats/min. ± SE                                                                      Ouabain dose,                                              Dose      5 min. after adm.                                                                      μg/kg ± SE, inducing          Compound            N  mg/kg iv                                                                           O-value                                                                            of test compound                                                                       arrhythmia                                                                          asystole                      __________________________________________________________________________    Control             13 --   326 ± 10                                                                        --       175 ±  7                                                                         289 ± 11,1                 Propranolol         3  1    280 ± 17                                                                        219 ± 240 ±  5.sup.xx                                                                  363 ± 11.sup.xx                                3  3    293 ± 17                                                                        238 ± 14                                                                            295 ± 35.sup.x                                                                   435 ± 24.sup.xx                                5  6    301 ± 10                                                                        206 ± 269 ± 39.sup.x                                                                   418 ± 34.sup.x             Phthalimidoethanesulfone amide                                                                    1  12   333  330      170   220                           Phthalimidoethanesulfone methylamide                                                              2  6    261 ± 45                                                                        255 ± 51                                                                            188 ± 17                                                                         345 ± 20                                       2  12   369 ± 30                                                                        399 ± 22                                                                            195 ± 15                                                                         265 ± 50                   Phthalimidoethanesulfone ethylamide                                                               2  3    332 ± 22                                                                        332 ± 16                                                                            175 ±  5                                                                         318 ± 22                                       1  6    285  270      150   360                           Phthalimidoethanesulfone n-propylamide                                                            2  2    229 ± 34                                                                        243 ± 18                                                                            165 ± 10                                                                         272 ± 27                                       2  3    286 ± 55                                                                        294 ± 45                                                                            160 ± 10                                                                         322 ± 62                   Phthalimidoethanesulfone isopropylamide                                                           2  3    321 ± 39                                                                        312 ± 27                                                                            197 ± 32                                                                         297 ± 27                                       1  6    303  291      155   290                           Phthalimidoethanesulfone n-butylamide                                                             1  3    210  213      175   340                                               2  6    256 ± 19                                                                        256 ± 43                                                                            200 ±  0.sup.x                                                                   382 ± 37                   Phthalimidoethanesulfonyl acetamide                                                               2  1    292 ±  1                                                                        316 ± 10                                                                            185 ±  5                                                                         307 ±  2                                       3  3    260 ± 9                                                                         259 ± 10                                                                            215 ± 24                                                                         355 ± 20.sup.x                                 4  6    329 ± 15                                                                        334 ± 11                                                                            212 ± 16                                                                         345 ± 26                                       5  12   329 ± 19                                                                        349 ± 19                                                                            210 ± 16                                                                         360 ± 13.sup.x             __________________________________________________________________________     .sup.x p < 0.05                                                               .sup.xx p < 0.01                                                         

The effects of the compounds on the CNS were studied in mice. Therotating rod method (N. W. Dunham and T. S. Miya, J. Am. Pharm. Assoc.54, 208, 1957) was used for studying motor coordination. For all thetested compounds TD₅₀ (the dose at which 50 percent of the animals felloff the rod) was always higher than the anticonvulsive ED₅₀ (the dosepreventing convulsions in 50 percent of the animals). Although nosedative effect could be observed in these tests,hexobarbiturate-induced sleep was prolonged in mice after administrationof those test compounds which were found to have an anticonvulsiveaction. 2-Phthalimidoethane sulfonylacetamide, which had anantiarrhythmic but no anticonvulsive effect, did not prolong the time ofsleep.

The hot plate method (P. A. J. Janssen & A. Jagenau, J. Pharm.Pharmacol. 13, 513, 1957) did not reveal any analgesic effect on mice.The test compounds had no diuretic effect on unanesthetized rats nor anyeffect on the blood circulation in normotensive uretane-anesthetizedrats. The compounds were found to be atoxic; LD₅₀ in mice after oraladministration was >2 g/kg.

I claim:
 1. A method of treating epilepsy in a mammal afflictedtherewith, said method comprising administering to said mammal atherapeutically effective amount of a compound with the chemicalstructure: ##STR9## where R₁ =HR₂ =ethyl-,n-propyl-,isopropyl, orn-butylor where ##STR10##
 2. A method according to claim 1 wherein saidcompound is administered orally or intraperitoneally.
 3. A method oftreating arrythmia in a mammal afflicted therewith, said methodcomprising administering to said mammal a therapeutically effectiveamount of a compound with the chemical structure: ##STR11## where R₁=HR₂ =ethyl-,n-propyl-,isopropyl, or n-butylor where ##STR12##
 4. Amethod according to claim 3 wherein said compound is administeredintravenously.